Blockade of MCU-Mediated Ca 2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation.

Autor:	Tomar D; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Jaña F; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Dong Z; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Quinn WJ 3rd; Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Jadiya P; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Breves SL; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Daw CC; Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Srikantan S; Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Shanmughapriya S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Nemani N; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Carvalho E; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Tripathi A; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Worth AM; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Zhang X; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Razmpour R; Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Seelam A; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Rhode S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Mehta AV; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Department of Biology, Temple University, Philadelphia, PA 19122, USA., Murray M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Slade D; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Ramirez SH; Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Mishra P; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Gerhard GS; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Caplan J; Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA., Norton L; Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA., Sharma K; Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Rajan S; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA., Balciunas D; Department of Biology, Temple University, Philadelphia, PA 19122, USA., Wijesinghe DS; Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA., Ahima RS; Division of Endocrinology, Diabetes and Metabolism, John Hopkins University School of Medicine, Baltimore, MD 21287, USA., Baur JA; Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Madesh M; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA. Electronic address: muniswamy@uthscsa.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2019 Mar 26; Vol. 26 (13), pp. 3709-3725.e7.
DOI:	10.1016/j.celrep.2019.02.107
Abstrakt:	Mitochondrial Ca 2+ uniporter (MCU)-mediated Ca 2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCU Δhep ) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca 2+ ( m Ca 2+ ) uptake, delays cytosolic Ca 2+ ( c Ca 2+ ) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCU Δhep were a direct result of extramitochondrial Ca 2+ -dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca 2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCU Δhep hepatocytes. Conversely, gain-of-function MCU promotes rapid m Ca 2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca 2+ dynamics to hepatic lipid metabolism. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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